NOTCH SIGNALING IN MAMMALIAN CELLS

Summary

Principal Investigator: GERALDINE WEINMASTER
Abstract: DESCRIPTION: Members of the Notch/LIN-12/GLP-1 family of transmembrane receptors are believed to play a central role in development by regulating cell-fate decisions in invertebrates. The applicant has isolated several genes encoding Notch receptors and Notch ligands from rat, and has been studying their expression and function to address the molecular mechanism of Notch signaling during mammalian development. Notch is associated with malignancies, suggesting a role for maintaining an undetermined state during normal development, and Notch is also involved in human disorders of stroke and dementia (CADASIL and Alzheimer's disease), suggesting a role outside of development as well. Experiments proposed are based on the applicant's previous findings, and are logical extensions designed to answer a number of basic questions concerning Notch function. They will determine if Notch functions as a dimer or monomer, and if ligand activation of Notch involves ligand dimerization. They also will explore how Notch cell surface expression is regulated and investigate the hypothesis that Notch is cleaved and transported to the nucleus following ligand binding. In contrast to what has been reported for the invertebrate systems, they made the surprising observation that the mammalian ligands are not equal in their ability to activate the different Notch receptors. Based on these observations, they have designed experiments to identify sequences present in the ligands and receptors that account for the observed ligand specificity. In addition, they will explore the production and use of soluble forms of Notch ligands to study Notch signaling. They found that Notch signaling leads to activation of both CBF1-dependent and CBF1-independent pathways. Preliminary data indicate that the CBF1-dependent pathway positively regulates the expression of Notch. They will investigate the molecular mechanisms underlying this positive feedback system. They will also examine the possibility of reciprocal signaling in the ligand-expressing cell following ligand-receptor interactions. Together the experiments proposed in this grant will provide new information on the structure/function requirements of Notch-ligand interactions and thereby extend our present understanding of mammalian Notch signaling.
Funding Period: 1994-01-01 - 2003-07-31
more information: NIH RePORT

Top Publications

  1. pmc Fringe glycosyltransferases differentially modulate Notch1 proteolysis induced by Delta1 and Jagged1
    Liang Tung Yang
    Department of Biological Chemistry, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA 90095 1737, USA
    Mol Biol Cell 16:927-42. 2005
  2. ncbi The extracellular matrix protein MAGP-2 interacts with Jagged1 and induces its shedding from the cell surface
    Leslie C Nehring
    Department of Medicine, Division of Pulmonary and Critical Care Medicine, Washington University, St Louis, Missouri 63110, USA
    J Biol Chem 280:20349-55. 2005
  3. pmc The divergent DSL ligand Dll3 does not activate Notch signaling but cell autonomously attenuates signaling induced by other DSL ligands
    Ena Ladi
    Department of Biological Chemistry, Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, USA
    J Cell Biol 170:983-92. 2005
  4. ncbi Microfibrillar proteins MAGP-1 and MAGP-2 induce Notch1 extracellular domain dissociation and receptor activation
    Alison Miyamoto
    Department of Biological Chemistry, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095, USA
    J Biol Chem 281:10089-97. 2006
  5. pmc DSL ligand endocytosis physically dissociates Notch1 heterodimers before activating proteolysis can occur
    James T Nichols
    Department of Biological Chemistry, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA 90095, USA
    J Cell Biol 176:445-58. 2007
  6. ncbi Notch signaling--constantly on the move
    James T Nichols
    Department of Biological Chemistry, David Geffen School of Medicine, UCLA, 650 Charles Young Drive South, Los Angeles, CA 90095, USA
    Traffic 8:959-69. 2007
  7. pmc Selective use of ADAM10 and ADAM17 in activation of Notch1 signaling
    Esra Cagavi Bozkulak
    Department of Biological Chemistry, David Geffen School of Medicine, UCLA, Los Angeles, California 90095, USA
    Mol Cell Biol 29:5679-95. 2009

Scientific Experts

  • GERALDINE WEINMASTER
  • James T Nichols
  • Alison Miyamoto
  • Christine Yao
  • Liang Tung Yang
  • Esra Cagavi Bozkulak
  • Patrick W Hein
  • J Michael Shipley
  • Ena Ladi
  • Leslie C Nehring
  • Samantha L Olsen
  • Brendan D'Souza
  • Rhiana Lau
  • Jim Boulter
  • Weihong Ge
  • Jennifer O Manilay
  • Chris Kintner
  • Yi E Sun
  • Ellen A Robey

Detail Information

Publications7

  1. pmc Fringe glycosyltransferases differentially modulate Notch1 proteolysis induced by Delta1 and Jagged1
    Liang Tung Yang
    Department of Biological Chemistry, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA 90095 1737, USA
    Mol Biol Cell 16:927-42. 2005
    ....
  2. ncbi The extracellular matrix protein MAGP-2 interacts with Jagged1 and induces its shedding from the cell surface
    Leslie C Nehring
    Department of Medicine, Division of Pulmonary and Critical Care Medicine, Washington University, St Louis, Missouri 63110, USA
    J Biol Chem 280:20349-55. 2005
    ....
  3. pmc The divergent DSL ligand Dll3 does not activate Notch signaling but cell autonomously attenuates signaling induced by other DSL ligands
    Ena Ladi
    Department of Biological Chemistry, Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, USA
    J Cell Biol 170:983-92. 2005
    ..Finally, together with the modulator lunatic fringe, Dll3 altered N signaling levels that were induced by other DSL ligands...
  4. ncbi Microfibrillar proteins MAGP-1 and MAGP-2 induce Notch1 extracellular domain dissociation and receptor activation
    Alison Miyamoto
    Department of Biological Chemistry, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095, USA
    J Biol Chem 281:10089-97. 2006
    ..Together these results demonstrate for the first time that the microfibrillar proteins MAGP-1 and MAGP-2 can function outside of their role in elastic fibers to activate a cellular signaling pathway...
  5. pmc DSL ligand endocytosis physically dissociates Notch1 heterodimers before activating proteolysis can occur
    James T Nichols
    Department of Biological Chemistry, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA 90095, USA
    J Cell Biol 176:445-58. 2007
    ..Based on our findings, we propose that mechanical forces generated during DSL ligand endocytosis function to physically dissociate hNotch, and that dissociation is a necessary step in Notch activation...
  6. ncbi Notch signaling--constantly on the move
    James T Nichols
    Department of Biological Chemistry, David Geffen School of Medicine, UCLA, 650 Charles Young Drive South, Los Angeles, CA 90095, USA
    Traffic 8:959-69. 2007
    ..In particular, endocytosis and membrane trafficking of DSL ligands, Notch and modulators can determine the competence of cells to send or receive signals that ensure reproducibility in generating cell types regulated by Notch signaling...
  7. pmc Selective use of ADAM10 and ADAM17 in activation of Notch1 signaling
    Esra Cagavi Bozkulak
    Department of Biological Chemistry, David Geffen School of Medicine, UCLA, Los Angeles, California 90095, USA
    Mol Cell Biol 29:5679-95. 2009
    ..We propose that in addition to exposing the ADAM cleavage site, activating N1 conformational changes facilitate selective cleavage by specific proteases...